1. Technical Field
The invention relates to an improved method for making nevirapine, and to several novel intermediates which are produced during the course of carrying out the improved method.
2. Background Information
Nevirapine is a non-nucleoside inhibitor of HIV reverse transcriptase, which is useful in the treatment of HIV infection in humans. The chemical name for nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2xe2x80x2, 3xe2x80x2-e][1,4]diazepin-6-one. Its structural formula is: 
The earliest known synthesis of nevirapine, by Hargrave et al., is described in U.S. Pat. No. 5,366,972. The synthetic method employed is depicted in the following reaction Scheme 1. 
In the method of Hargrave et al., 2-chloronicotinoyl chloride is formed by reacting 2-chloronicotinic acid with thionyl chloride. Next, as shown in Scheme 1, the reaction of 2-chloronicotinoyl chloride with 2-chloro-4-methyl-3-pyridinamine produces 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide. This is reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide. The final step is the cyclization to produce nevirapine, which occurs on treatment of the final intermediate with sodium hydride.
A refinement of the above process, described by Schneider et al. in U.S. Pat. No. 5,569,760, is presently used for the commercial manufacture of nevirapine. In this improvement of the synthesis, the reaction of 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide with cyclopropylamine is carried out in the presence of a neutralizing agent, which is an oxide or hydroxide of an an element of the second main or second subgroup of the periodic table. It is preferred to use as the neutralizing agent an oxide or hydroxide of an alkaline earth metal or of zinc, with calcium oxide being particularly preferred.
While the synthesis provided by U.S. Pat No. 5,366,972 is the best known to date, it nevertheless suffers from several significant drawbacks. First, because the reaction of cyclopropylamine with 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide is carried out at elevated temperature (between 130xc2x0 to 150xc2x0 C.) and because cyclopropyl amine is so highly volatile, this reaction must be carried out in a high pressure reaction vessel. Second, 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide becomes thermally unstable above about 145xc2x0 C., and allowing the temperature of the reaction mixture to go above this temperature poses the risk of an explosion. Therefore, it is prudent to carefully control the temperature of the reaction mixture so that it remains below 145xc2x0 C. until substantially all of this material has been consumed by the reaction. Maintaining such tight control of the temperature of the reaction mixture is difficult at best, and it is made all the more difficult by the fact that the reaction is itself exothermic. Third, it is necessary to remove the neutralizing agent by filtration. Finally, due to the production of side products, the overall yield of the synthesis is only about 25%.
There is thus a need for a better synthesis for nevirapine.
The present invention satisfies this need by providing a synthesis for nevirapine that is safer, higher yielding and more economical than any method yet known.
The improved synthesis of nevirapine provided by the present invention is depicted below in reaction Scheme 2. 
In the first reaction step, a 2-halo-3-pyridinecarbonitrile (1) of the formula 
wherein X is a fluorine, chlorine, bromine or iodine atom, preferrably chlorine or bromine, is reacted with cyclopropylamine (2), to yield 2-(cyclopropylamino)-3-pyridinecarbonitrile (3). This reaction is carried out in an inert, organic solvent, with or without water, at elevated temperature. Appropriate organic solvents are C1 to C6 straight or branched chain alcohols, tetrahydrofuran, dimethylformamide, diglyme, toluene, and the like. The preferred solvents are ethanol and 1-propanol, with or without water. Optionally, a base, either organic or inorganic, such as triethylamine, diisopropylethylamine, potassium phosphate, sodium carbonate, potassium carbonate and the like, can be added as an acid scavenger. The reaction can be carried out at a temperature between ambient temperature and reflux temperature, but it is preferred that the temperature be between 77xc2x0 and 100xc2x0 C.
The 2-(cyclopropylamino)-3-pyridinecarbonitrile is next hydrolyzed to yield 2-(cyclopropylamino)-3-pyridine carboxylic acid (4), which predominantly exists as the zwitterion when isolated according to the disclosed procedures and is, therefore, represented as such in Scheme 2. Isolation of the nitrile prior to hydrolysis is optional. The hydrolysis of the nitrile to the carboxylic acid can be carried out in a conventional manner, using a strongly acidic or basic solution. The hydrolysis is preferrably carried out using an aqueous mixture of hydrogen peroxide and a strong base, such as sodium or potassium hydroxide, or an aqueous mixture of a strong base, such as sodium or potassium hydroxide, and an alcohol of 1 to 6 carbon atoms. Most preferrably, the hydrolysis is carried out using aqueous 1-propanol and potassium hydroxide. Heating to reflux will accelerate the rate of hydrolysis.
The 2-(cyclopropylamino)-3-pyridine carboxylic acid is next isolated from the reaction medium. This is conveniently accomplished by adjusting the pH to the isoelectric point, which is reached at about pH 6. This produces the zwitterion, which precipitates out and is then separated by filtration and dried. If an aqueous alcohol and a base are used to conduct the hydrolysis, the alcohol is first removed by distillation.
Subsequently, the 2-(cyclopropylamino)-3-pyridine carboxylic acid is treated with a chlorinating agent, to yield 2-(cyclopropylamino)-3-pyridinecarbonyl chloride (5). Appropriate chlorinating agents are, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, and oxalyl chloride. The chlorination is performed in a manner known to those skilled in the art of organic synthesis. In general it is preferred to reflux the carboxylic acid (4) with the chlorinating agent, which will either be used neat or in solution with a suitable aprotic solvent such as, for example, toluene, acetonitrile, tetrahydrofuran, or the like. It is preferred to perform the chlorination by refluxing with neat thionyl chloride, any excess of which can later be conveniently removed by evaporation. As most chlorinating agents produce hydrochloric acid, the product (5) of this reaction step is depicted in Scheme 2 as the hydrochloride.
The 2-(cyclopropylamino)-3-pyridinecarbonyl chloride (5) is next reacted with a 2-halo-4-methyl-3-pyridinamine (6) of the formula 
wherein X is a fluorine, chlorine, bromine or iodine atom, preferrably chlorine or bromine. The most preferred reactant is 2-chloro-4-methyl-3-pyridinamind,. This produces an N-(2-halo-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide(7), wherein X is a fluorine, chlorine, bromine or iodine atom, preferrably chlorine or bromine. It is essential to first remove any remaining chlorinating agent, as this would react with the pyridineamine. If a highly volatile chlorinating agent, such as thionyl chloride, is used neat, then it may be removed by evaporation to leave the acid chloride (5) as a solid. If the chlorination is done in a solvent, then it is preferable to employ a solvent that is high boiling, so that chlorinating agent may be removed by evaporation, leaving the acid chloride dissolved in the solvent. In any event, the acid chloride (5) is to be maintained under anhydrous conditions. The acid chloride (5) and the pyridineamine (6) are reacted by dissolution in a suitable anhydrous solvent such as, for example acetonitrile, tetrahydrofuran, diglyme, dimethylformamide, dioxane, methylene chloride, or toluene. Optionally a base, either organic or inorganic, such as triethylamine, diisopropylethylamine, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium hydroxide, potassium hydroxide or the like, may be added to the reaction mixture as an acid scavenger. The reaction rate may be increased by heating up to the boiling point of the solvent.
Finally, the carboxamide (7) is cyclized to yield nevirapine. The cyclization is induced by treating the carboxamide (7) with a strong base, such as sodium hydride (NaH) r sodium bexamethyldisilazane (NaHMDS) in an inert anhydrous organic solvent, such as diglyme, toluene, or tetrahydrofuran, at from xe2x88x9230xc2x0 C. to 130xc2x0 C.
The synthesis of the intermediate 2-(cyclopropylamino)-3-pyridinecarbonitrile by means of the reaction of 2-chloro-3-pyridinecarbonitrile with cyclopropylamine is known from G. E. Hardtmann et al, J. Med. Chem. 1974, 17, 636.
The intermediates, 2-(cyclopropylamino)-3-pyridine carboxylic acid (4)and 2-(cyclopropylamino)-3-pyridinecarbonyl chloride (5) are believed to be novel and, thus, are considered to be aspects of the invention.
It is preferred to use 2-chloro-3-pyridinecarbonitrile as starting material (1) since syntheses for this substance are known and it is commercially available. Other 2-halo-3-pyridinecarbonitriles can be readily synthesized in an analogous manner.
Cyclopropylamine, the starting material (2), is also commercially available.
It is preferred to use 2-chloro-4-methyl-3-pyridinamine as reactant (6) since syntheses for this substance are known from U.S. Pat. Nos. 6,399,781; 5,686,618; 5,668,287; 5,654,429 and 5,200,522. Other 2-halo-4-methyl-3-pyridinamines can be readily synthesized in an analogous manner.